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South African Family Practice 2017; 59(1):24-29 S Afr Fam Pract Open Access article distributed under the terms of the ISSN 2078-6190 EISSN 2078-6204 Creative Commons License [CC BY-NC-ND 4.0] © 2017 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0 REVIEW

Guidelines for the Management of Vulgaris

W Sinclair

Head: Department of , University of the Free State, Bloemfontein Corresponding author, email: [email protected]

Abstract Background: Acne vulgaris is a very common that, in the vast majority, can and should be effectively managed by general medical practitioners. Several guideline documents for management thereof exist and there is an overwhelmingly large, confusing literature bank available on the topic.

Methods: This article summarises and simplifies the main guideline documents that have been published over the last few years to present the results in an algorithmic approach to the treatment of the different types and grades of acne.

Disclaimer: Adherence to these guidelines will not ensure successful treatment in every situation and should not be deemed inclusive of all proper methods of care or exclusive of other methods of care reasonably directed to obtaining the same results.

Introduction Pathogenesis of acne vulgaris

Acne vulgaris is the most common skin ailment in humans. It is Basic knowledge of the pathogenesis of acne is essential a chronic disease with potentially severe impact on the quality for practitioners, as treatment decisions have to be based on medication that will affect as many as possible of the of life of young people. Most cases are of mild severity and can factors involved. The more different pathogenetic factors are and should be managed by the general practitioner (GP). It is simultaneously addressed, the better the outcomes. On the therefore essential that GPs are well versed in the pathogenesis, other hand, two different drugs that address the same factors clinical diagnosis, grading of severity, treatment algorithm and will not have an additive effect. pharmacology of the medications used for acne. The below table outlines the relevant pathogenetic factors and The guidelines presented below are based on the latest the medications that will address each factor. documents generated by the Global Alliance for the Improvement There are numerous drugs that may worsen acne, mostly of Outcomes in Acne Treatment 20071 and 20092, as well as the hormonal preparations, and these should be discontinued as European Academy of Dermatology in 20123 and 2016.4 part of management. The most important ones are:

Table 1. Main pathogenetic factors in acne and corresponding treatments Pathogenetic Factor Relevant Medication Androgen stimulation of sebaceous glands ; Drosperinone Hypersecretion of sebum Oral Hyperkeratosis and occlusion of the duct that drains sebum into the hair Topical follicle The formation of the invisible microcomedo Topical retinoids Inflammatory mediators (Interleukin 1, etc.) released after stimulation of Topical retinoids; oral isotretinoin toll-like receptor 2 by Propionibacterium acnes Neutrophilic response to rupture of comedones and Oral cyclines; oral and topical ; oral macrolides induced by free fatty acids in sebum Proliferation of P. acnes Oral cyclines; oral macrolides; topical Inflammatory tissue damage by matrix metalloproteinases Oral cyclines

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• containing contraceptives like intramuscular medroxyprogesterone acetate or enanthate • Implantable progesterone (etonogestrel) pellets • Progesterone (levonorgestrel) releasing intra-uterine devices • Combination oral contraceptives that contain levonorgestrel as progestogen • Oral and topical • Anabolic steroids • Vitamin B12 (especially the high dose, intramuscular products) • Lithium • Diphenylhydantoin

Other factors that worsen acne are mostly related to overhydrating the skin with (unnecessary) oily moisturising creams and masks. A skin suffering from acne does not require moisturising at all, unless some other pathology is also present. Picture 2: Inflammatory papules and small pustules Clinical diagnosis of acne vulgaris

This is usually simple when basic rules are applied. It can present with varying numbers of open and closed comedones, inflammatory papules, pustules, nodules, , ulcers and scars. The face is practically always involved, the back and chest frequently, the arms and thighs rarely.

As a rule, comedones have to be present to be sure of the diagnosis, because there are several other conditions that may mimic acne, but their eruptions should not contain comedones. The only exception is acne induced by topical corticosteroids, which may show comedones, but it is not regarded as acne vulgaris.

Conditions that feature in the differential diagnosis of acne vulgaris are: • Acne • Steroid induced acne • Bacterial

• Pseudofolliculitis barbae Picture 3: Pustules • Eosinophilic folliculitis • Demodiccidosis • Papulonecrotic tuberculid • Folliculotropic cutaneous T-cell lymphoma.

Picture 1: Comedones Picture 4: Nodules and cysts www.tandfonline.com/oemd 25 The page number in the footer is not for bibliographic referencing 26 S Afr Fam Pract 2017;59(1):24-29

Grading of severity of acne vulgaris

This is essential as it will be the major parameter that will determine treatment choice. Several grading systems for acne are propagated, mostly based on series of photographs on which the severity is graded rather subjectively. This does not have much practical value and should not be used for treatment decisions.

Grading should be based on the types of lesions present, not on the number of lesions. For example: If only comedones are present, it is Grade 1 acne, even if there are 10 000 present; this will look very severe on a photograph, but the patient should still respond the same to topical retinoids as one with only 10 comedones and there will be no reason to use more potent or systemic treatment. Picture 5: Conglobate acne We thus propose the grading system in Table 2. It is easy to use, reproducible between observers and translates directly into treatment choices.5

Treatment algorithm for acne vulgaris4

Proposed treatment options for the different grades are as follows:

Grade1: Drug of choice: Topical retinoids (, or isotretinoin) Alternatives: Topical benzoyl peroxide; topical ; extraction for persistent, large comedones

These preparations should be applied daily over the whole of the affected areas and treatment should continue even after Picture 6: Ulcerating acne () clearance. “Spot treatment” is ineffective.

Grade 2: Method of choice: Topical retinoids plus antimicrobial preparations: - For superficial papules: Topical adapalene/benzoyl peroxide (BPO) combination product Alternatives: Topical at night, topical benzoyl peroxide in the morning; topical retinoid at night plus /benzoyl peroxide combination product in the morning.

Topical should never be used alone! - For deep papules: Topical retinoid plus oral cyclines: , or

Alternatives: Topical retinoids plus oral contraceptives Picture 7: Folliculotropic cutaneous T-cell lymphoma resembling acne that contain cyproterone acetate or drosperinone (for women only).

Table 2. Grading of acne severity Grade 1 Comedones only Grade 2 Comedones + red papules Grade 3 Comedones + red papules + pustules Grade 4 Comedones + red papules + pustules + nodules / cysts / conglobate lesions Acne fulminans The above + ulceration + fever and other systemic symptoms The presence of significant scarring places grading in the next higher category of severity.

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Topical retinoid plus oral macrolides for young patients can also be used, but such long-term use of topical antibiotics is or where unacceptable side-effects from cyclines were undesirable. found. Oral isotretinoin Topical retinoids plus dapsone as second line Present guidelines dictate strict indications for the use of this Systemic antibiotics should be used for a minimum of three drug. They are the following: months, but preferably not for longer than 4 months, to avoid • Grade 4 acne vulgaris the development of resistance. During the fourth • Lesser grades of acne, that failed treatment with: month, topical benzoyl peroxide or zinc should be added as anti-resistance agents. • Topical retinoids plus 3 months of oral cyclines, or Topical retinoids plus 4 cycles of oral contraceptives containing There is no scientific rationale for using antibiotics (topical or cyproterone acetate or drosperinone; systemic) as monotherapy. • Lesser grades of acne with significant scarring, to prevent Grade 3: Method of choice: Topical retinoids plus oral cyclines further scarring; note that OIT does not remove scarring and as mentioned above can worsen scarring in some individuals;

Alternatives: Topical retinoids plus combined oral • Dysmorphophobic patients who request the drug, especially contraceptives containing cyproterone acetate for when threatening self-harm; women. • Gram-negative folliculitis after prolonged antibiotic use.

Topical retinoids plus dapsone In Europe and the USA, oral isotretinoin may never be used Grade 4: Method of choice: Oral isotretinoin (OIT) as a full as first line treatment for acne vulgaris, but in South Africa we course (see below) may still use it in selected cases, as indicated above.

Alternatives: Topical retinoids plus combined oral Dosage of OIT: contraceptives containing cyproterone acetate, with added cyproterone acetate as 10 mg per day on days A full (potentially curative) course of this drug is administered at 5 – 19 of the menstrual cycle 0,5 – 1,0 mg/kg per day until a total cumulative dose of 120 mg Topical retinoids plus dapsone 100 mg per day per kg is reached. This can be extended to 150 mg/kg if the acne has not yet cleared. Maintenance treatment Cure is by no means guaranteed and one should never promise a After successful clearance of acne, maintenance treatment is patient a cure, because it happens in the minority of cases. almost always necessary. The only exception is where a full course of oral isotretinoin may have “cured” the condition, which There is no official maintenance dose for OIT, as mentioned happens in 38% of cases treated as such. Maintenance should above, but the South African guidelines allow for “pulse dosing” continue until the patient clearly never makes any new acne where 20 mg per day is used for the first 7 calendar days per lesions, on average at around 25 years of age. Acne continues month, indefinitely. after the age of thirty in 14% of cases and after forty in 1% of Prolonged “low dose” OIT is a form of maintenance dosing used patients. Maintenance can safely continue until then. mostly for convenience, is off-label, not supported by evidence, Topical retinoids are perfect for maintenance and are the only its safety has not been proven, has potentially serious side- products registered for this indication, as they effectively effects and in most cases, these patients could have been easily eradicate the invisible inflammatory and non-inflammatory maintained safely on topical retinoid combination products. microcomedones, the origins of all acne lesions. No other medication does this at present. Side-effects of OIT:

OIT is not registered for the maintenance treatment of acne Teratogenicity. This is the best known serious adverse and such use, commonly applied, is off-label and at present not effect; “retinoid embryopathy” results in many cardiovascular, defensible. The most common reason for this inappropriate use neurological and limb defects. The risk is high (as for ), of OIT is the neglect to use topical retinoids correctly. the effect is pharmacological and independent of dosage, and is thought to last up to 1 month after stopping the drug, after Topical retinoids can be combined with topical BPO (as a single which pregnancy is safe.6 combination product) or separately if the patient continues to make superficial inflammatory papules. BPO alone is poor Mucocutaneous side-effects. Initial worsening of acne; xerosis maintenance because it does not remove microcomedones and and ; retinoid ; epistaxis; staphylococcal does not have anti-inflammatory effects like the retinoids do. infections of the skin, often of the nail folds, to cause ; Azelaic acid would be the third choice for maintenance if topical pyogenic granulomas of the nail folds are often seen on the toes; retinoids cannot be tolerated. BPO/clindamycin combination hypertrophic scarring and keloids.6 www.tandfonline.com/oemd 27 The page number in the footer is not for bibliographic referencing 28 S Afr Fam Pract 2017;59(1):24-29

Ocular complications. Dry eyes that can persist indefinitely; : Blue light therapy has become popular and blepharoconjunctivitis; with corneal ulceration (rare); undoubtedly has some benefit, but hardly ever as monotherapy. recent use of isotretinoin is a contraindication to laser refractive It has not been proven to be equal to or more effective than eye surgery. Decreased night vision is a common and potentially the conventional drugs outlined above and it is very costly. dangerous side-effect, making driving a vehicle at night One important indication for this method is acne in pregnancy, hazardous and is the reason why aviation pilots may not use the where we cannot use any retinoids, the preferred antibiotics or drug. Night blindness can persist indefinitely.6 anti-androgens.

Laboratory abnormalities. enzyme disturbance; raised Moisturisers and masks: These have no value and usually serum lipids (especially ).6 worsen the acne; should be avoided.

Central abnormalities. Raised intracranial orally: This can be effective, but in toxic doses; oral pressure – isotretinoin must not be combined with or isotretinoin is much safer and more effective. vitamin A. Mood disturbance, , inability to concentrate Strategy to follow when a patient fails to respond and study can occur as uncommon, unpredictable, idiosyncratic favourably events requiring prompt action. The FDA recommends close monitoring of patients treated with isotretinoin for symptoms Non-drug related reasons: 4 of depression or suicidal thoughts, irritability, anger, loss of • Severe seborrhoea (oiliness) – consider more potent face wash pleasure or interest in sports activities, sleeping too much or • Check (again) exposure of patient to acne-provoking agents/ too little, changes in weight or appetite, decreased school or drugs work performance, trouble concentrating, mood disturbance, • Check stress and diet – consider lower glycaemic diet or aggression. (FDA Alert for Healthcare Professional 07/2005).7 • Check comedogenicity of facial make-up and moisturizing cream – avoid altogether Musculoskeletal abnormalities. and arthralgia occur • Macrocomedones – mechanically remove comedones more frequently in patients who also engage in heavy exercise, seen in 2 - 5% of cases. CK-levels may become markedly raised. • SignificantP. acnes component – change to retinoid/BPO fixed Diffuse interosseous skeletal hyperostosis can occur after combination prolonged use. Premature closure of epiphyses is possible. • P. acnes resistance – change to oral isotretinoin • Gram-negative folliculitis – change to oral isotretinoin Gastro-intestinal side-effects. Some studies found that isotretinoin can cause ulcerative , while others deny it.8 • Endocrine abnormality (see below) – investigate and address.

Precautions to be taken before initiation of OIT Drug-related reasons: 4 treatment: • Females: Check (again) type of contraception – change if • All patients (male and female) have to sign an information necessary, as indicated above sheet where the side-effects and dangers of the drug are • Retinoid may be inappropriate for skin type or environmental pointed out and where they undertake to comply with conditions – change retinoid formulation from gel to cream contraceptive directives. (dry climates) or cream to gel (humid climates) • All patients: Liver enzymes (AST, ALT and GGT) and fasting • Retinoid concentration may be too low – change to higher total cholesterol and triglycerides have to be normal. concentration of retinoid • Female patients: Pregnancy test has to be negative. • Check type and dose of oral antibiotic – correct if needed Effective contraception has to start immedi- ately. • Oral isotretinoin taken on empty stomach – ensure drug is First tablets are taken on the third day of the taken with a fatty meal next normal menstrual period. • Initial flare of acne on isotretinoin – temporarily lower dose Precautions during treatment OIT: and/or add low dose prednisone for two weeks. • Effective contraception throughout and up to one month after Poor adherence: 4 the last tablets were taken. • Check if treatment was only applied to spots – patient • Liver enzymes and lipids as above after one month; if normal education to use correctly again, it need not be repeated during the rest of the treatment. • Infrequent application – check frequency and quantity used Adjunctive therapies per month • Infrequent use of oral drug – check frequency of taking oral Comedo extraction: This is often done to remove treatment macrocomedones, especially after the use of OIT. For other indications, it has little value if not combined with topical • Adverse events – check and address if necessary retinoids. • Patient misunderstands drug effects – educate patient. www.tandfonline.com/oemd 28 The page number in the footer is not for bibliographic referencing Guidelines for the Management of Acne Vulgaris 29

Adverse events: When to refer to a dermatologist • Retinoid irritation – reduce frequency of application to Acne cases should preferably be referred in the following alternative days or change to lower concentration of retinoids situations: or different formulation (change gel to cream) • All cases of acne fulminans (ulcerating acne) • Overuse of cleansers – use cleanser with pH around 5, infrequently • Nodulocystic acne with scarring, especially • Possible contact dermatitis and photosensitivity – investigate • Underlying endocrine abnormalities • Gastric side-effects of cyclines – take with a meal (will not • Uncertain diagnosis significantly alter effectivity). • Severe treatment-related adverse events When to investigate for underlying endocrine • Recalcitrant papulopustular or nodular acne. abnormality Conclusion This is sometimes justified in female patients, especially in cases of severe or recalcitrant acne. It is hardly ever relevant in males. It is hoped that this brief summary and algorithm will present Routine endocrine investigations are not warranted. a practical management strategy for acne vulgaris in general practice. If applied, this may contribute to great improvement in Investigations for hyperandrogenism are warranted when the the outcomes of acne treatment. following are present: • Menstrual abnormalities References 1. Strauss JS, Krowchuk DP, Leyden JJ, et al. Guidelines of care for acne vulgaris • Age of onset after 25 years management. J Am Acad Dermatol. 2007;56(4):651-63. • Other signs of polycystic ovary syndrome 2. Thiboutot D, Gollnick HP, Bettoli V, et al. New insights into the management of • acne: An update from the Global Alliance to Improve Outcomes in Acne Group. J Am Acad Dermatol. 2009;60(5):S1-S50. • Acanthosis nigricans and lipoatrophy 3. Nast A , Dreno B, Bettoli V, et al. European evidence-based (S3) guidelines for the • Virilisation treatment of acne. J Eur Acad Dermatol Venereol. 2012;26 Suppl 1:1-29. 4. Gollnick H, Bettoli V, Lambert J, et al. A consensus-based practical and daily Baseline investigations should then include: guide for the treatment of acne patients. J Eur Acad Dermatol Venereol. • Thorough physical, including gynaecological, history and 2016;30:1480-90. examination 5. Sinclair W, Jordaan HF. Acne Guidelines 2005 update. S Afr Med J. 2005;95:883-92. • Blood tests, including levels of total serum testosterone, 6. Sinclair W. The rational use of systemic isotretinoin: a call for moderation. S Afr dehydroepiandrosterone sulphate (DHEAS), LH, FSH, fasting Med J. 2012; 102(5):282-4. glucose, HBa1c, serum cortisol, serum lipids 7. Goodfield MJD, Cox NH, Browser A, et al. Advice on the safe introduction • Appropriate imaging for ovarian and adrenal pathology. and continued use of isotretinoin in acne in the UK, 2010. Br J Dermatol. 2010;162:1172-9. Any abnormalities discovered should be managed or referred 8. Shale M, Kaplan GG, Panaccione R, Ghosh R. Isotretinoin and intestinal appropriately. inflammation: what gastroenterologists need to know. Gut. 2009;58:737-41.

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